CN106278964A - The preparation method of florfenicol - Google Patents
The preparation method of florfenicol Download PDFInfo
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- CN106278964A CN106278964A CN201610641153.3A CN201610641153A CN106278964A CN 106278964 A CN106278964 A CN 106278964A CN 201610641153 A CN201610641153 A CN 201610641153A CN 106278964 A CN106278964 A CN 106278964A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation method of a kind of florfenicol, belong to the technical field of pharmaceutical synthesis.The preparation method of the florfenicol of the present invention, with D D-4-methylsulfonylphserine serine ethyl ester as raw material, prepares through reduction reaction, ring-closure reaction, fluorination reaction and hydrolysis.Described fluorination reaction is with dichloromethane solvent, and with cyclised products, fluorination reagent as reaction raw materials, wherein said cyclised products is 1.25～1.30: 1 with the mass ratio of fluorination reagent.The preparation method of the present invention has that technological operation is simple, the advantage of low cost, the by-product of fluorination reaction is decreased by the control of reaction condition and the use of additive, the method making the present invention just can get, merely through a step decolouring and purification step, the florfenicol product that purity is high, impurity is few, be conducive to controlling product cost, improve production efficiency.
Description
Technical field
The present invention relates to the technical field of pharmaceutical synthesis, it is more particularly related to the preparation of a kind of florfenicol
Method.
Background technology
Florfenicol is also known as Florfenicol, Florfenicol etc., for the animal specific broad spectrum antibiotic of a new generation, its structure
It is similar to thiamphenicol, but its antibacterial ability is up to 10 times more than of thiamphenicol, and its has a broad antifungal spectrum, bactericidal action is strong
Greatly, safe and efficient, particularly without the induced aplastic anemia effect of chloromycetin antibiotics, therefore it is widely used.At present,
Have more than 20 state approval in the world and allow it to sell use.Florfenicol has been approved for pig, fowl, fish etc. at home
Many animals.
Nineteen ninety-five, US5382673A (Jon E.Clark) discloses the synthesis technique of a kind of florfenicol, and it utilizes
Ishikawa reagent achieves the process of a step primary hydroxyl fluorination, has an advantage that preparation technology is simple, easy and simple to handle, but fluorine
Agent cost is high, and it is miscellaneous to generate MSM enzyme element etc. after causing follow-up hydrolysis owing to the side reaction of fluorination reaction is more
Matter, and by-product color is deeper.Through solvent recovery, washing separates, dry, decolour and crystallizes be centrifuged after color be yellow
Even brown, needs to obtain, through refined further, the florfenicol product that purity is higher.
Summary of the invention
In order to solve above-mentioned technical problem of the prior art, it is an object of the invention to provide the system of a kind of florfenicol
Preparation Method.
In order to realize foregoing invention purpose, a first aspect of the present invention have employed techniques below scheme:
The preparation method of a kind of florfenicol, it is with D-D-4-methylsulfonylphserine serine ethyl esterFor raw material, through reduction reaction, ring-closure reaction, fluorination reaction and water
Solution reaction prepares.
Wherein, described reduction reaction is with methanol as solvent, with D-D-4-methylsulfonylphserine serine ethyl ester with potassium borohydride is
Reaction raw materials, described D-D-4-methylsulfonylphserine serine ethyl ester is preferably 4.3～4.5: 1 with the mass ratio of potassium borohydride.
Wherein, described reduction reaction is carried out at 45～58 DEG C.
Wherein, described ring-closure reaction is with glycerol as solvent, with reduzateTwo chloroacetonitriles and glacial acetic acid are raw material, wherein said reduzate,
The mass ratio of two chloroacetonitriles and glacial acetic acid is 4.70～4.80: 1.90～1.95: 1.
Wherein, described ring-closure reaction is carried out at 47～48 DEG C.
Wherein, described fluorination reaction is with dichloromethane solvent, with cyclised products
Fluorination reagent is reaction raw materials, and wherein said cyclised products is 1.25～1.30: 1 with the mass ratio of fluorination reagent.
Wherein, described fluorination reaction is carried out at 102～103 DEG C.
Wherein, described fluorination reagent is with dichloromethane as solvent, is cooled to below freezing be passed through hexafluoro third at diethylamine
Alkene gas prepares, and wherein said hexafluoropropene is 1.70～1.80: 1 with the mass ratio of diethylamine.
Wherein, described fluorination reaction is also added with 2,2,3,3-tetrafluoro propanoic acid, described fluorination reagent and described 2,2,3,
The mass ratio of 3-tetrafluoro propanoic acid is 1: 0.03～0.05.
Wherein, described hydrolysis is with fluorinated productPreparation is reacted with water
Obtain florfenicol
Compared with prior art, the preparation method of the florfenicol of the present invention has the advantages that
The preparation method of the present invention has that technological operation is simple, the advantage of low cost, by the control of reaction condition with add
The use adding agent decreases the by-product of fluorination reaction so that the method for the present invention is decoloured merely through a step when industrialized production
The florfenicol product that purity the most available with purification step is high, impurity is few, is conducive to controlling product cost, improves and produce effect
Rate.
Accompanying drawing explanation
Fig. 1 is the preparation technology route sketch of the florfenicol of the present invention.
Detailed description of the invention
Below with reference to specific embodiment, the preparation method of florfenicol of the present invention is further elaborated, with
Help those skilled in the art that inventive concept, the technical scheme of the present invention are had more complete, accurate and deep understanding.
The preparation technology route of the florfenicol of the present invention is as shown in Figure 1: mainly include reductive ring closure, fluorination hydrolysis and essence
Step processed.The operation of reductive ring closure reaction includes: puts into methanol in pot, open stirring.Then D-is put into methylsulfonyl benzene silk
Propylhomoserin ethyl ester and potassium borohydride.Open jacket steam, temperature rising reflux.Recovered under reduced pressure methanol is to syrupy shape.Add glycerol, glacial acetic acid
With two chloroacetonitriles, insulation.Insulation terminates, and is cooled to room temperature.Centrifugal, wash with isopropanol.Drying, discharging, enter dry, obtain cyclization
Thing.The operation of fluorination hydrolysis includes: put into dichloromethane and diethylamine in pot.Open stirring, cool down material (-10 with liquid N2
～-30 DEG C), it is passed through hexafluoroethylene, obtains fluorination reagent.Difluoromethane and cyclocomplex is put in fluorination pot.By fluorination reagent
Press-in fluorination pot, and be incubated.After insulation terminates, material is pressed into hydrolyzer, reclaims dichloromethane.To material to syrupy shape, add
Enter methanol, sodium acetate.Reclaim methanol, add isopropanol backflow.Recovered under reduced pressure isopropanol.Cool down, be centrifuged, wash, enter to dry, obtain
Florfenicol crude product.Refined operation includes: put into isopropanol, purified water and florfenicol crude product in Decolouring pot successively.Open
Opening stirring, add activated carbon, temperature rising reflux decolours, filter pressing, removes carbon slag.Open chuck brine ice, by mother solution freezing and crystallizing.From
The heart, purified water washing, discharging, enter dry, obtain florfenicol finished product.
Embodiment 1
In reactor, put into methanol (solvent), open stirring and then put into D-D-4-methylsulfonylphserine serine ethyl ester
(495.0kg) with potassium borohydride (114.0kg), jacket steam intensification (in reactor 50～58 DEG C) backflow is opened.Add 900kg
Glycerol is replaced, and then decompression (water rushes pump) recovery methanol becomes syrupy shape to material, adds glacial acetic acid (85kg), two chloroethenes afterwards
Nitrile 210kg is incubated (47.-48 DEG C, 18h).Insulation end is cooled to room temperature, then reduce pressure (water rushes pump, and ammonia enters pump, after condensation outside
Row).Dissolving with ethanol (95%, 1200kg), rear cooling (20 DEG C) centrifugal filtration (is added a cover, logical exhaust device), and filtrate is predominantly
Ethanol and glycerol, redistillation reclaims ethanol and applies mechanically, vinasse (useless glycerol).Filter cake add water (1000kg) rinsing, dry, go out
Material, enters drying room (steam heats for airpillow-dry, air blast) and dries to obtain cyclocomplex.The conversion ratio of described reduction reaction is 95～96%,
Ring-closure reaction conversion ratio is 92～93%.
Dichloromethane (canned, to squeeze into head tank with pump) and diethylamine (108.9kg, barreled, packaging is put in reactor
Empty drum store set-point, squeezes into head tank with pump, and the air that head tank displaces absorbs with dilute hydrochloric acid after condensing out).Open
Open stirring, with liquid N2 (coil pipe) cooling material (temperature be-10～-30 DEG C).It is passed through hexafluoropropene (gaseous state, 188.1kg), obtains fluorine
Agent.Difluoromethane 300kg and cyclocomplex 346.5kg is put in fluorination pot.In fluorization agent is pressed into autoclave and be incubated
(102 DEG C, dichloromethane vaporization pressurization).Insulation terminates, and gained fluoride is pressed into hydrolysis kettle, reclaims dichloromethane to material extremely
Syrupy shape, adds the sodium acetate (regulation pH to 5.0) of recovery.Reclaim methanol and alcohol mixeding liquid, add refinement mother liquor and heat up
70 DEG C of backflow 4h, recovered under reduced pressure isopropanol.Cooling, centrifugal, washing, obtain the layering of florfenicol crude product centrifugal liquid, and water layer is predominantly
Water and sodium acetate, enter waste water and enter waste water processing station.It is 92～93% that fluorination hydrolysis produces yield.
Refine in Decolouring pot, put into isopropanol, purified water and florfenicol crude product successively.Open stirring, add activated carbon.
Heat up 82 DEG C of isopropanol reflux decolours, removes carbon slag through filter.Filtrate is depressed into crystallization kettle, opens chuck saline, by filtrate
Freezing and crystallizing, centrifugal filtration, purified water washing (filtrate and washings return to top hydrolysis), discharging, enter drying room (airpillow-dry)
Drying to obtain florfenicol finished product, when using HPLC to detect florfenicol, recording product purity is 94.8～96.0%, adopts
Calculate with peak area normalization method, it is possible to find the area of single impurity peaks is up to 0.5～1.0%.
Embodiment 2
In reactor, put into methanol (solvent), open stirring and then put into D-D-4-methylsulfonylphserine serine ethyl ester
(495.0kg) with potassium borohydride (114.0kg), jacket steam intensification (in reactor 50～58 DEG C) backflow is opened.Add 900kg
Glycerol is replaced, and then decompression (water rushes pump) recovery methanol becomes syrupy shape to material, adds glacial acetic acid (85kg), two chloroethenes afterwards
Nitrile 210kg is incubated (47-48 DEG C, 18h).Insulation end is cooled to room temperature, then reduce pressure (water rushes pump, and ammonia enters pump, after condensation outside
Row).Dissolving with ethanol (95%, 1200kg), rear cooling (20 DEG C) centrifugal filtration (is added a cover, logical exhaust device), and filtrate is predominantly
Ethanol and glycerol, redistillation reclaims ethanol and applies mechanically, vinasse (useless glycerol).Filter cake add water (1000kg) rinsing, dry, go out
Material, enters drying room (steam heats for airpillow-dry, air blast) and dries to obtain cyclocomplex.The conversion ratio of described reduction reaction is 95～96%,
Ring-closure reaction conversion ratio is 92～93%.
Dichloromethane (canned, to squeeze into head tank with pump) and diethylamine (108.9kg, barreled, packaging is put in reactor
Empty drum store set-point, squeezes into head tank with pump, and the air that head tank displaces absorbs with dilute hydrochloric acid after condensing out).Open
Open stirring, use liquid N2(coil pipe) cooling material (temperature be-10～-30 DEG C).It is passed through hexafluoropropene (gaseous state, 188.1kg), obtains fluorine
Agent.Difluoromethane 300kg, 2,2,3,3-tetrafluoro propanoic acid 11.2kg and cyclocomplex 346.5kg are put in fluorination pot.Will fluorination
Agent press-in autoclave is interior and is incubated (102 DEG C, dichloromethane vaporization pressurization).Insulation terminates, and gained fluoride is pressed into hydrolysis kettle,
Recovery dichloromethane, to material to syrupy shape, adds the sodium acetate (regulation pH to 5.0) of recovery.Reclaim methanol and ethanol mixing
Liquid, adds 70 DEG C of backflow 4h of refinement mother liquor intensification, recovered under reduced pressure isopropanol.Cooling, centrifugal, washing, obtain florfenicol crude product from
Heart liquid is layered, and water layer is mainly water and sodium acetate, enters waste water and enters waste water processing station.Fluorination hydrolysis produce yield be 94～
96%.
Refine in Decolouring pot, put into isopropanol, purified water and florfenicol crude product successively.Open stirring, add activated carbon.
Heat up 82 DEG C of isopropanol reflux decolours, removes carbon slag through filter.Filtrate is depressed into crystallization kettle, opens chuck saline, by filtrate
Freezing and crystallizing, centrifugal filtration, purified water washing (filtrate and washings return to top hydrolysis), discharging, enter drying room (airpillow-dry)
Drying to obtain florfenicol finished product, when using HPLC to detect florfenicol, recording product purity is 98.2～99.1%, adopts
Calculate with peak area normalization method, it is possible to find the area of single impurity peaks less than 0.1% (purification operations that embodiment 2 uses with
Embodiment 1 is identical).
For the ordinary skill in the art, the present invention is simply exemplarily described by specific embodiment,
Obviously the present invention implements and is not subject to the restrictions described above, as long as the method design that have employed the present invention is entered with technical scheme
The improvement of various unsubstantialities of row, or the most improved design by the present invention and technical scheme directly apply to other occasion
, all within protection scope of the present invention.
Claims (9)
1. a preparation method for florfenicol, it is with D-D-4-methylsulfonylphserine serine ethyl esterFor raw material, anti-through reduction reaction, ring-closure reaction, fluorination reaction and hydrolysis
Should prepare.
The preparation method of florfenicol the most according to claim 1, it is characterised in that: described reduction reaction is to be with methanol
Solvent, with D-D-4-methylsulfonylphserine serine ethyl ester and potassium borohydride as reaction raw materials, described D-D-4-methylsulfonylphserine serine ethyl ester
It is preferably 4.3～4.5: 1 with the mass ratio of potassium borohydride.
The preparation method of florfenicol the most according to claim 2, it is characterised in that: described reduction reaction is at 45～58 DEG C
Carry out.
The preparation method of florfenicol the most according to claim 1, it is characterised in that: described ring-closure reaction is with glycerol
For solvent, with reduzateTwo chloroacetonitriles and glacial acetic acid are raw material, wherein
The mass ratio of described reduzate, two chloroacetonitriles and glacial acetic acid is 4.70～4.80: 1.90～1.95: 1.
The preparation method of florfenicol the most according to claim 4, it is characterised in that: described ring-closure reaction is at 47～48 DEG C
Carry out.
Wherein, described fluorination reaction is with dichloromethane solvent, with cyclised productsWith
Fluorination reagent is reaction raw materials, and wherein said cyclised products is 1.25～1.30: 1 with the mass ratio of fluorination reagent.
The preparation method of florfenicol the most according to claim 5, it is characterised in that: described fluorination reaction is 102～103
DEG C carry out.
The preparation method of florfenicol the most according to claim 5, it is characterised in that: described fluorination reagent is with dichloromethane
Alkane is solvent, is cooled to the hexafluoropropene gas that is passed through below freezing at diethylamine and prepares, wherein said hexafluoropropene and two
The mass ratio of ethamine is 1.70～1.80: 1.
The preparation method of florfenicol the most according to claim 5, it is characterised in that: described fluorination reaction has been also added with
2,2,3,3-tetrafluoro propanoic acid, described fluorination reagent is 1: 0.03～0.05 with the mass ratio of described 2,2,3,3-tetrafluoro propanoic acid.
The preparation method of florfenicol the most according to claim 1, it is characterised in that: described hydrolysis is to be fluorinated product
ThingReact with water and prepare florfenicol
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108329240A (en) * | 2018-03-27 | 2018-07-27 | 深圳蓝新科技有限公司 | The preparation method of florfenicol midbody |
| CN109456238A (en) * | 2018-12-19 | 2019-03-12 | 栎安化学(上海)有限公司 | A kind of preparation method of florfenicol midbody thiamphenicol amine |
| WO2019091179A1 (en) * | 2017-11-10 | 2019-05-16 | 和鼎（南京）医药技术有限公司 | Method for preparing florfenicol intermediate v and method for preparing florfenicol using intermediate v |
| CN113402475A (en) * | 2021-06-07 | 2021-09-17 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate |
| CN116496190A (en) * | 2023-06-28 | 2023-07-28 | 山东国邦药业有限公司 | Preparation method of florfenicol |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019091179A1 (en) * | 2017-11-10 | 2019-05-16 | 和鼎（南京）医药技术有限公司 | Method for preparing florfenicol intermediate v and method for preparing florfenicol using intermediate v |
| CN109776364A (en) * | 2017-11-10 | 2019-05-21 | 和鼎（南京）医药技术有限公司 | The preparation method of florfenicol midbody V a kind of and Florfenicol preparation method using intermediate V |
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| CN109456238A (en) * | 2018-12-19 | 2019-03-12 | 栎安化学(上海)有限公司 | A kind of preparation method of florfenicol midbody thiamphenicol amine |
| CN113402475A (en) * | 2021-06-07 | 2021-09-17 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate |
| CN116496190A (en) * | 2023-06-28 | 2023-07-28 | 山东国邦药业有限公司 | Preparation method of florfenicol |
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